Toxicology

1. Toxicology Industrial Hygiene IENG 341 Carter J. Kerk Industrial Engineering Department SD School of Mines Spring 2008

2. Assignment • Read Nims, Chapter 2 • HW2 • Critical Thinking Questions • P. 46-47 • 1-5 • Due Date?

3. Definitions • Toxicity: The ability of a substance to cause harm or adversely affect an organism • Toxicology: The science and study of harmful chemical interactions on living tissue

4. Occupational Toxicology • Workplace exposure to chemicals • You or someone you know has probably experienced an episode of toxicology • Injury or death due to: • Smoke inhalation • Confined space incident • Ingestion or absorption of a chemical

5. The Dose-Response Relationship • A time of exposure (dose) to a chemical, drug, or toxic substance, will cause an effect (response) on the exposed organism • If the amount or intensity of the dose increases, there will be a proportional increase in the response

6. Definitions • Dose: The amount of a substance administered (or absorbed), usually expressed in milligrams of substance per kilogram of the exposed organism (mg/kg) • Response: The effect(s) of a substance; may be positive or negative

7. Dose – Response Curve

8. Acute and Chronic Terminology: Exposure as well as Response • We previously discussed acute and chronic exposure • Acute exposure: short time / high concentration • Chronic exposure: long-term, low concentration • Acute response: rash, watering eyes, cough from brief exposure to ammonia • Chronic response: emphysema from years of cigarette smoking

9. Possible Response Levels • No response: at low dosage levels there may be no response at all • Threshold dose: the lowest level of dosage at which a response is manifested • NOAEL: no observed adverse effect level • NEL: no effect level • Above threshold dose: response can be positive up to a point and then could become toxic to the organism • Different people or organisms will exhibit a variety of responses

11. Indicators of Relative Toxicity • Toxicity: ability of a substance to cause harm or have an adverse affect • How much harm? • What aspect of the population? • Notation: • LD, lethal dose • LC, lethal concentration • ED, effective dose • EC, effective concentration

12. LD50 – a measure of relative toxicity • Most common toxicity notation • Determined in the lab and based on an acute exposure to adult test animal • Lethal dose that produces death in 50% of the exposed population • LD50, 35 mg/kg, oral, rat • 35 mg of dose per kg of rat’s body weight, when administered orally, produces death in 50% of exposed population • Comparing the LD50 between two substances gives the relative toxicity between the two substances

13. LD50 Relative Toxicity

14. Example of Toxicity Classification

15. Effect of route of administration

16. Toxicity variance between organisms (Pesticide: chlorfenvinfos)

17. How can we interpret animal test? • Animal tests can give an indication of relative toxicity which can be extrapolated to humans • Problems • Toxicity variance between organisms • Animal doses (strength or time) may be higher than realistic human exposures • On a body weight basis, humans are usually more susceptible to toxic effects, sometimes by a factor of ten • Therefore, human interpretation requires use of a safety factor

18. Epidemiological Studies • Prospective epidemiological study • Take a cohort (or group of individuals) with a common exposure • Follow through time to see if they develop disease • Retrospective epidemiological study • Take a cohort with a disease and trace back through time to see if there is a common exposure • These are difficult with many confounding factors, but are quite valuable

19. Latency Period • Long delay between exposure and disease • Some diseases may not develop for many years • Lung cancer may occur as much as 30 years after exposure to asbestos • This makes animal studies and epidemiological studies even more difficult, but also very valuable

20. Toxicity data limitations • Although there is considerable toxicity data available, for most chemicals it is still limited • Less than 10% of the thousands of chemicals have regulatory or recommended standards for safe exposure

21. Routes of Exposure • Inhalation • Ingestion • Absorption through the skin • Less common • Injection • Absorption through eyes and ear canals

23. Inhalation • Most common route of entry into body • Therefore our area of highest concern • Lungs are designed for efficient gas exchange between the air and bloodstream • Lungs have up to 1000 square feet of exchange area (about 32 feet by 32 feet) • Normal day’s breathing volume: 8 cu ft • Therefore great potential for toxins to enter bloodstream • ACB Respiratory System: 91, 96

25. Skin Absorption (2nd most important route) • Skin surface area is about 20 square feet (4.5 ft by 4.5 ft) • Compare to 1000 sq ft for lungs • Materials can be absorbed into blood stream just below the skin surface or toxins can be stored in fat deposits • Obviously workers can easily expose their hands into solvents, oils, chemicals, etc., plus these materials can be sprayed or rubbed on other parts of the body • Many chemicals are either soluble in water or in oil (fat, lipid) • The skin easily absorbs lipid-soluble materials • Solvents • Water-soluble materials are not easily absorbed • Lipid layer on skin provides a barrier • ACB Skin: 161

27. Ingestion (3rd most important route) • Ingestion is not usually intentional • Unintentional ingestion • Failure to wash hands and face before meals • Eating/drinking in areas where airborne hazards exist • Lighting cigarettes with dirty hands • Application of cosmetics • Use of chewing tobacco or gum in contaminated areas

28. Ingestion • The digestive tract is moist and designed for efficient absorption • Surface area of intestines is greatly increased by small projections (villi) • Thin surfaces, highly vascularized • Materials easily transferred to bloodstream • ACB Digestive System: 98, 104

30. Injection • Less common • Possible hazards • Outdoor work, construction sites, hazardous waste sites, plants, animals, reptiles, insects, abrasions, puncture wounds, cuts

31. Absorption into eyes and ears • Much less common but possible • Moist surfaces

32. Distribution of Toxins • Once toxins are in the body, there are several mechanism of movement and action • Inhalation • Toxics may enter bloodstream • Toxics may irritate or scar lung tissues directly • Skin Absorption • Toxics may enter bloodstram • Toxics may irritate, corrode or burn skin directly

33. Once absorbed into the body, toxins can move to other tissues and organs through various ways: • Filtration • Toxins move through membrane pores • Diffusion • Movement from higher concentration to lower concentration • Active transport • Movement across a membrane otherwise impermeable by a transport mechanism • Chemical reaction or carrier molecule, requires energy • Phagocytosis • Toxins “eat” or engulf other cells or by use of white blood cells

34. Biotransformation & Excretion of Toxins • Water soluble substances: easily to eliminate • Lipid soluble substances are difficult to eliminate • Biotransformation: process by which materials are chemically altered to make them easier to eliminate (as in lipid soluble substances) • Biotransformation and excretion through the liver • Filtration and excretion through the kidneys • Therefore, liver and kidneys are useful in eliminating toxins from the body, but on the other hand become target organs of toxins because of their nature

36. Liver • Important in metabolism, energy storage, protein synthesis • Receives blood from digestive tract and works to concentrate, transform, and excrete substance (both good and bad [toxins]) • Thus produces bile (enriched) which is returned to the intestines • ACB Digestive System: 106

38. Hepatoxic Effects • Hepatoxic = “liver toxins” • Necrosis = cell death • Steatosis = intercellular fat accumulation, fatty liver • Cholestasis = interference with the production of bile and biliary excretion • Immune cell infiltrate = presence of abnormally high numbers of immune cells • Neoplasia = cancer • Cirrhosis = fibrosis, collagen fibers deposited throughout liver • Causes: chronic alcoholism, hepatitis • Collagen • interferes with normal function and the internal architecture • a protein-based connective tissue that is not normally present in the liver • Normally found as a component of tendons, ligaments, and bones

40. Kidneys • Receive 25% of cardiac output for filtration • Primarily for elimination of water soluble molecules • Large molecules (proteins) and lipid soluble materials are reabsorbed through the tubules of the nephron • Nephron = functional unit of the kidney (see next slide • Materials pass by filtration, diffusion, active transport • ACB Urinary System: 108, 110-112

42. Classes of Toxins and Toxic Responses • Irritants and Sensitizers • Systemic Toxins • Neurotoxins • Reproductive Toxins • Carcinogens

43. Irritants • Localized, some physical damage • To skin, eyes, respiratory system • Corrosion – most severe response • Ulceration, tissue damage, usually permanent • E.g., chemical burns from acids and bases • Acute irritations • Redness, inflammation, usually reversible

44. Sensitizers • Substances that stimulate a response from the immune system, usually the second exposure • Triggering exposure can be extremely low dose • Immune system – recognize and reject foreign objects in the body, including infectious disease and hazardous materials • Allergic reaction releases antibodies to attack • Reaction ranges from skin rash to anaphylactic shock (life threatening)

45. Systemic Toxins • Toxins that affect target organs • Vinyl chloride – liver (cancer) • Cadmium – kidney • Benzene – blood marrow (leukemia) • Toxicity mechanism is often related to the normal function of the target organ

46. Neurotoxins • Compounds that negatively affect the nervous system • Response can be mild to severe • Effects can impact thinking ability, motor control, regulation of breathing and heartbeat • Central Nervous System [CNS] (brain, spinal cord) • Coordination, emotion, speech, memory • Peripheral Nervous System [PNS] (all but brain, spinal cord) • Sensory info (touch, heat/cold, proprioception, pain) • Motor impulses (movement) • Autonomic Nervous System [ANS] • heart rate, breathing, organ control, reflexes • Neurotoxins can produce neuropathy – a toxic effect characterized by progressive decline and death of nerves

49. Reproductive Toxins • Substances that affect the reproductive process • May affect males, females, or both • Lead • Males – decreased numbers of sperm or defective sperm • Pregnant Females – can cause deformities in developing fetus, especially fetus’ developing nervous system • Teratogens (Greek: monster) – toxins that cause abnormal development or birth defects

50. Thalidomide (a teratogen) • Originally prescribed as a sedative and specifically advertised for safe use by pregnant women • Thousands of babies were born between 1959 and 1962 with severe deformities (no legs, arms, deformed ears, etc.) • Popular use in Europe and Canada • Use in US was delayed for FDA studies which later proved its danger